Ischemic heart disease (IHD) and ischemic strokes are a major problem with our aging society and are the most common causes of death in most Western countries, and a major cause of hospital admissions.
During a heart attack or failure, reduced blood supply to the heart muscle can lead to severe tissue damage and death. Prompt reperfusion of ischemic tissue is critical for restoring normal function. However, this return of blood flow can paradoxically produce a progressive destruction of reversibly damaged cells, thereby leading to tissue dysfunction and infarction. This “reperfusion injury” has multifactorial causes of disease but appears to be strongly associated with an inflammatory response; with the return of blood flow, several inflammatory processes may occur to potentiate ischemic injury, including leukocyte adhesion and infiltration and the release of reactive oxidative species (ROS) such as oxygen free radical species and peroxides, for example H2O2.
Diabetic cardiomyopathy (DCM) is an increasingly recognized cause of congestive heart failure among diabetic patients. Oxidative stress is one of the common pathological changes associated with the development of DCM leading to the maladaptation of the left ventricular remodelling processes, manifested as abnormal cardiac function and can lead to ischaemia of the heart tissue.
Ischaemia can be caused by a variety of conditions. For example, acute incidents such as stroke, myocardial infarction or mechanical trauma, and chronic conditions such as atherosclerosis, peripheral vascular disease and diabetes can cause ischaemia. Hypertension is another type of disorder that can lead to ischaemia.
Following an acute incident such as a heart attack caused by a blocked coronary artery, various drugs are delivered intravenously to the heart attack victim to assist in removing any blood vessel obstruction thus re-establishing blood flow leading to reperfusion of tissues. However, this type of treatment is not directed to preventing or ameliorating the tissue damage associated with reperfusion. Creating an environment for reperfusion to occur and re-establish the supply of oxygen to tissue can lead to increased tissue damage by increasing free radical production.
Conventional treatments for subjects exhibiting ischaemia or at risk of ischaemia are inadequate and effective treatment regimes are urgently required.
One approach for preventing and/or mitigating the damage caused by ischaemia/reperfusion injuries has been to administer compounds which have antioxidant properties. For example, the synthetic flavonoid, 3′,4′-dihydroxy flavonol (DiOHF) has been demonstrated to reduce infarct and injury associated with myocardial ischaemia and reperfusion during in vitro studies (Shen Wang, Gregory Dusting, Clive May and Owen Woodman, British Journal of Pharmacology (2004) 142, 443-452), but has poor pharmacokinetic properties.
Previous attempts to improve the pharmacokinetics of flavonoid compounds have focussed on the attachment of solubilising groups on the flavonoid ring. See for example, WO 2006/094357 Entitled “Flavonoid compounds and uses thereof” which describes improving the water solubility of a number of flavonoid compounds.
The poor pharmacokinetics of many flavonoids has severely limited their therapeutic usefulness. These characteristics limit their applicability to therapies where acute parenteral administration is desirable, for example in vasodilation therapies. Moreover, the use of other routes of administration, for example, oral, has been limited by the properties of the available flavonoid compounds.
Flavonoid compounds have the following general structure:

There is therefore a need for novel flavonoid compounds that have good biological activity and improved pharmacokinetic properties.